Is C3 p.Glu586= (c.1758G>A) pathogenic?

C3 p.Glu586= (c.1758G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0493%, mid); Associated with complement component 3 deficiency.

What condition is associated with C3 p.Glu586= (c.1758G>A)?

C3 p.Glu586= (c.1758G>A) is associated with complement component 3 deficiency, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Glu586= (c.1758G>A) in the general population?

C3 p.Glu586= (c.1758G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

How is Complement component 3 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

C3 p.Glu586=

c.1758G>A · rs764201055 · VCV330320

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

complement component 3 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.5
Overall
CADD	7.206	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00657% 106/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Admixed American	0.01%	10,000
European (non-Finnish)	0.00771%	12,967
African / African-American	0.00667%	14,985
Remaining individualsnot grpmax-eligible	0.0016%	62,486

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: C3
Protein: p.Glu586=
Coding: c.1758G>A
MANE Select: NM_000064
dbSNP: rs764201055
Type: single nucleotide variant
Location: chr19:6709771 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 586: a β-strand; a disulfide bond

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 9 atypical hemolytic-uremic syndrome with C3 anomaly

For Complement component 3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

C3 p.Glu586Ala Uncertain significance ★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T Likely pathogenic ★★ same condition
C3 c.4030-2A>G Likely pathogenic ★★ same condition
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same condition
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c3-p-glu586 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown